Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycogen synthase kinase-3 (GSK-3) is regulated by various extracellular ligands and phosphorylates many substrates, thereby regulating cellular functions. Using yeast two-hybrid screening, we found that GSK-3beta binds to AKAP220, which is known to act as an A-kinase anchoring protein. GSK-3beta formed a complex with AKAP220 in intact cells at the endogenous level. Cyclic AMP-dependent protein kinase (PKA) and type 1 protein phosphatase (PP1) were also detected in this complex, suggesting that AKAP220, GSK-3beta, PKA, and PP1 form a quaternary complex. It has been reported that PKA phosphorylates GSK-3beta, thereby decreasing its activity. When COS cells were treated with dibutyryl cyclic AMP to activate PKA, the activity of GSK-3beta bound to AKAP220 decreased more markedly than the total GSK-3beta activity. Calyculin A, a protein phosphatase inhibitor, also inhibited the activity of GSK-3beta bound to AKAP220 more strongly than the total GSK-3beta activity. These results suggest that PKA and PP1 regulate the activity of GSK-3beta efficiently by forming a complex with AKAP220.
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PMID:A-kinase anchoring protein AKAP220 binds to glycogen synthase kinase-3beta (GSK-3beta ) and mediates protein kinase A-dependent inhibition of GSK-3beta. 1214 1

Glycogen synthase kinase-3beta (GSK3beta) plays important roles in metabolism, embryonic development, and tumorigenesis. Here we investigated the role of GSK3beta signaling in vascular biology by examining its function in endothelial cells (ECs). In EC, the regulatory phosphorylation of GSK3beta was found to be under the control of phosphoinositide 3-kinase-, MAPK-, and protein kinase A-dependent signaling pathways. The transduction of a nonphosphorylatable constitutively active mutant of GSKbeta promoted apoptosis under the conditions of prolonged serum deprivation or the disruption of cell-matrix attachments. Conversely, the transduction of catalytically inactive GSK3beta promoted EC survival under the conditions of cellular stress. Under normal cell culture conditions, the activation of GSK3beta signaling inhibited the migration of EC to vascular endothelial growth factor or basic fibroblast growth factor. Angiogenesis was inhibited by GSK3beta activation in an in vivo Matrigel plug assay, whereas the inhibition of GSK3beta signaling enhanced capillary formation. These data suggest that GSK3beta functions at the nodal point of converging signaling pathways in EC to regulate vessel growth through its control of vascular cell migration and survival.
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PMID:Regulation of angiogenesis by glycogen synthase kinase-3beta. 1216 28

Glycogen synthase kinase-3 (GSK-3) is a highly conserved serine/threonine protein kinase that is involved in the signal transduction cascades of multiple cellular processes. GSK-3 has two isoforms, designated alpha and beta. GSK-3beta protein levels and GSK-3 enzyme activity have been reported to be reduced by over 40% in postmortem frontal cortex of schizophrenic patients. GSK-3 is also present in peripheral tissue such as lymphocytes. In this study we aimed to find whether the reduction in brain GSK-3beta measures is reflected in peripheral tissue of schizophrenic patients. Fresh lymphocytes from schizophrenic patients showed no difference in GSK-3 alpha and GSK-3beta mRNA levels, GSK-3beta protein levels, or total GSK-3 (alpha+beta) enzyme activity compared with findings in control subjects. In addition, lymphocyte-derived cell lines from schizophrenic patients did not differ in their GSK-3beta protein levels from levels in normal control subjects. The results rule out the use of lymphocyte GSK-3 as a marker for central GSK-3 abnormalities in schizophrenia.
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PMID:GSK-3 parameters in lymphocytes of schizophrenic patients. 1237 50

Glycogen synthase kinase-3 (GSK-3) is a ubiquitous cytosolic serine/threonine protein kinase that has been implicated in multiple receptor-mediated intracellular processes. Its unique feature, which distinguishes it from other protein kinases, is that it is constitutively active in resting conditions and acts as a suppressor of signalling pathways. The fact that the function of two key targets of insulin action, glycogen synthase and insulin receptor substrate-1, are suppressed by GSK-3, as well as the fact that GSK-3 activity is higher in diabetic tissues, makes it a promising drug discovery target for insulin resistance and Type 2 diabetes. Thus, the development of GSK-3 inhibitors has received attention as an attempt to control both the spread of the disease and its severity.
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PMID:The role of glycogen synthase kinase-3 in insulin resistance and type 2 diabetes. 1238 79

Intracellular regulation of oocyte meiosis is not completely understood. However, reversible phosphorylation, which involves serine/threonine protein kinases and phosphatases (PP), is an important mediator. Glycogen synthase kinase-3 (GSK-3) is a highly conserved serine/threonine protein kinase. Currently no reports exist on presence or function of GSK-3 in mammalian oocytes. The aim of this study was to determine GSK-3 presence/absence, transcript and protein expression, intracellular protein distribution, and to investigate the functional importance of GSK-3 in mouse oocyte meiosis. Germinal vesicle-intact (GVI) oocytes contained both GSK-3 transcript and protein. Although GSK-3 beta-isoform is the only transcript identifiable in GVI oocytes, both alpha- and beta-isoforms were recognized by Western blot analysis. In growing, meiotic-incompetent oocytes GSK-3 was present, diffusely located throughout the cytoplasm and absent in the nucleus, whereas in meiotic-competent oocytes this cytoplasmic GSK-3 displays a predominant peri-oolemma staining. Treatment of mouse GVI oocytes with lithium chloride (LiCl), which inhibits both inositol monophosphatase (IMPase) and GSK-3, had no significant influence on oocyte viability, morphology, or development to metaphase II (MII). However, LiCl caused abnormal spindle formation and significantly increased incidence of abnormal homologue segregation during the first meiotic division. L690,330, which is a specific IMPase inhibitor, had no significant effect on oocyte viability, morphology, MII development, or homologue segregation. This is the first report of GSK-3 in mammalian oocytes. LiCl inhibition of mouse oocyte GSK-3 modified organization of microtubules and/or function of meiotic spindles thus compromising segregation of condensed bivalent chromosomes.
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PMID:Glycogen synthase kinase-3 regulates mouse oocyte homologue segregation. 1242 Mar 4

Glycogen synthase kinase 3beta (GSK3beta) is an essential protein kinase that regulates numerous functions within the cell. One critically important substrate of GSK3beta is the microtubule-associated protein tau. Phosphorylation of tau by GSK3beta decreases tau-microtubule interactions. In addition to phosphorylating tau, GSK3beta is a downstream regulator of the wnt signaling pathway, which maintains the levels of beta-catenin. Axin plays a central role in regulating beta-catenin levels by bringing together GSK3beta and beta-catenin and facilitating the phosphorylation of beta-catenin, targeting it for ubiquitination and degradation by the proteasome. Although axin clearly facilitates the phosphorylation of beta-catenin, its effects on the phosphorylation of other GSK3beta substrates are unclear. Therefore in this study the effects of axin on GSK3beta-mediated tau phosphorylation were examined. The results clearly demonstrate that axin is a negative regulator of tau phosphorylation by GSK3beta. This negative regulation of GSK3beta-mediated tau phosphorylation is due to the fact that axin efficiently binds GSK3beta but not tau and thus sequesters GSK3beta away from tau, as an axin mutant that does not bind GSK3beta did not inhibit tau phosphorylation by GSK3beta. This is the first demonstration that axin negatively affects the phosphorylation of a GSK3beta substrate, and provides a novel mechanism by which tau phosphorylation and function can be regulated within the cell.
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PMID:Axin negatively affects tau phosphorylation by glycogen synthase kinase 3beta. 1242 63

Glycogen synthase kinase 3 (GSK-3) is a protein kinase that plays essential roles in the control of several developmental, metabolic, and apoptotic processes. Owing to its negative actions on several oncogenic insults, it has been considered a putative functional tumor suppressor. We studied the expression, activity, and localization of GSK-3beta during the process of chemically induced two-stage mouse skin carcinogenesis and also in the tumors generated upon subcutaneous injection of Akt-transformed keratinocytes. We found that GSK-3 activity was downregulated at the later stages of promotion by tyrosine 216 dephosphorylation and serine 9 phosphorylation. The data obtained with Akt-transformed keratinocytes clearly suggested the involvement of Akt in serine 9 phosphorylation of GSK-3beta. Finally, besides functional inactivation, significant basal activity of GSK-3beta was detected in all cases, indicating that this enzyme provides essential functions to malignant keratinocytes.
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PMID:Expression, localization, and activity of glycogen synthase kinase 3beta during mouse skin tumorigenesis. 1248 9

Glycogen synthase kinase (GSK)-3beta is a conserved serine/threonine protein kinase highly abundant in brain tissue. A dominant mechanism by which cells react to stress involves GSK-3beta. We studied the effect of stress on GSK-3beta levels ex vivo. We have previously found reduced GSK-3beta protein levels and GSK-3 activity in postmortem prefrontal cortex of schizophrenic patients. Since schizophrenic patients experience stress more severely than healthy people, we questioned whether their GSK-3beta reduction is stress-related using a rat model. Rats were exposed to acute, subchronic, or chronic stress using brief cold restraint. No effect was found on frontal cortex GSK-3beta protein levels. These results suggest that reduction in GSK-3beta levels in schizophrenic patients is not affected by cold restraint stress and supports the possibility that the changes observed in postmortem brains may be related to the disease.
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PMID:Lack of effect of acute, subchronic, or chronic stress on glycogen synthase kinase-3beta protein levels in rat frontal cortex. 1250 18

Glycogen synthase kinase-3 (GSK-3) was shown to be a key factor in attenuation of the cellular action of insulin. We speculated that inhibition of GSK-3 might have a potential therapeutic value in treatment of insulin resistance and type 2 diabetes. Here, we present a novel class of specific phosphorylated peptides inhibitors of GSK-3, which in sharp contrast to other protein kinase inhibitors that are ATP analogs, are substrate-competitive. We show that the GSK-3 peptide inhibitor activated glycogen synthase activity 2.5-fold in human embryonic kidney 293 cells, and increased glucose uptake in primary mouse adipocytes in the absence or presence of insulin compared with cells treated with two respective peptide controls. In addition, an i.p. administration of GSK-3 peptide inhibitor to normal or insulin-resistant obese C57BL/6J mice, improved their performance on glucose tolerance tests compared with control-treated animals. We present here a novel rational strategy for developing specific GSK-3 inhibitors and point toward GSK-3 as a promising therapeutic target in insulin resistance and type-2 diabetes.
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PMID:Insulin mimetic action of synthetic phosphorylated peptide inhibitors of glycogen synthase kinase-3. 1262 60

Glycogen synthase (GS) catalyses the incorporation of uridine diphosphate-glucose into glycogen in skeletal muscle. In concert with the glucose transport step, GS activity is thought to be rate-limiting in the disposal of glucose as muscle glycogen. Glycogen synthase is regulated by both allosteric factors (primarily glucose 6-phosphate) and covalent modification by reversible phosphorylation and dephosphorylation leading to inactivation and activation of GS, respectively. Exercise activates both stimulatory and inhibitory regulators of GS and it is thought that the resultant activity of GS during exercise depends on the relative strength of opposing signals. However, the mechanisms by which exercise regulates GS activity are not fully understood. Glycogen breakdown, the GM-protein phosphatase 1 complex and possibly cellular relocalization of GS may be considered important factors involved in the stimulation of GS activity during exercise, while adenosine monophosphate-activated protein kinase and plasma adrenaline (via protein kinase A) can be considered as essential for the exercise-induced inhibitory signals to GS.
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PMID:Regulation of glycogen synthase in skeletal muscle during exercise. 1286 35


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